synthetic chemistry

Molecular Mechanics

Synthesising small molecular machines has been somewhat limited to making molecules that can walk or spin round cogwheels. Mind you that is still pretty impressive. Now things are set to change with a recent publication in Science by Dr Leigh from the University of Manchester in the UK.

The Manchester group synthesised a rotaxane (a molecular ring) threaded through an axle that consists of peptides. The rotaxane has a thiolate moiety that removes the amino acids in sequence and transfers them to the site of the new growing peptide chain. There is a wonderful summary in C&E News, with an interesting video of how it all works.

The group used 1018 machines in parallel to generate milligram quantities of a single sequence peptide. This mimics the ribosome in its valuable function in the generation of peptides. The “arm” picks up the amino acid by a transacylation reaction and delivers them to a different place on the ring.

There are still some problems to be solved, for example the rather slow reaction rate as the ring needs about 12 hours to make the amide bonds. Compare this to the 15-20 bonds per second produced by the ribosome itself. There are a few other problems, and no doubt they are being addressed at this moment. However this paper and the technology are impressive and will probably have a great future.

Imagine what several moles of these could do once things become optimised, producing peptides of any sequence one desired, natural or unnatural. This is a fascinating concept and I look forward to seeing lots more appearing on this system.

The Flagship of Chemistry (Total Organic Synthesis).

In an essay to celebrate the 125th anniversary of Angewandte Chemie our friend and mentor Prof. K. C. Nicolaou had penned an essay for this august event. Which can be seen here.

Not to be outdone in this essay he examines the flow of chemical knowledge from its emergence in the 5th century B.C. to the present day, 2,500 years or so. Stopping along the way of this long journey, he highlights the leading scientific personalities of each age together with their theorems discoveries.

Emerging out of this primordial soup of chemical knowledge is the science of organic synthesis the “Flagship” of which is “the art of total synthesis”. This “Flagship” was launched in the 19th century and sat in the harbour for quite a few decades until the scientists of the day got their collective acts together and came up with atomic theory. I suppose somehow like hitchhikers in the galaxy. Indeed in 1845 two of these eminent thinkers and, more importantly experimentalists put their heads together and came up with the answer to the ultimate question, and it was not “24”.

Laurent and Gerhardt started to unfurl the sails of the flagship, which had been sitting there gathering dust, recognising that the molecules synthesised to that day could be classified into a “homologous” box and a “type” box, the latter assuming that all organic molecules belonged to three different types. This suggestion paved the way for the connection between inorganic and organic chemistry. Kekulé was also busy on the organic side of the Flagship, thinking about structure and writing his 2-volume book “The Chemistry of Benzene Derivatives or the Aromatic Substances”. Much later on Pauling refined these theories in his book “The Nature of the Chemical Bond”. Which I suppose puts him in the middle of the “Flagship”.

Back to Kekulé; in 1860 together with Canizzaro he organised what must have been one of the first international conferences to deal with all the currently contentious ideas of chemistry, so the crew was assembling, with some dissention. But they did agree on atomic weights and chemical formulas. Indeed this august meeting inspired one participant, Mendeléev that he went home and came up with the periodic table.

The “Flagship” hauled anchor around the late half of the 18th century with work by Scheele (isolation) and Wöhler (synthesis). Liebig and his students also populated the crew refining many ideas of the day. Based on the new science of synthesis new industries sprang up. Perkin, trying to synthesise quinine actually obtained the first dyestuff. More of these were prepared and indeed it was said that the wealth of a nation could be measured in the value of Her dyestuff industry. It was a relatively short step from dyes to pharmaceuticals, Aspirin, introduced by Bayer, being the example.

Synthetic organic chemistry emerged as the driving force of the “Flagship” with many new reactions being discovered, mainly from German laboratories and by students or students of students of Liebig. This was helped along its way by the role of the structure of the various compounds. This vital part of chemistry is just as important today as it was then. I suppose the Admiral of the “Flagship” has to be R. B. Woodward, with numerous captains in tow not to mention a successor, E. J. Corey.

Everything considered I found this to be a very interesting perspective on the evolution of organic synthesis and especially the total synthesis of complex molecules. Prof. Nicolaou has done an excellent job in linking the various scientific discoveries over the years to a subject dear to his heart. If you are interested in the timeline of synthesis it is well worth a read.

More Development Adventures: The Nozaki-Hiyama-Kishi Reaction

The NHK reaction is nicely described in this Wiki article. Catalytic amounts of nickel were found to be beneficial in this system and Kishi used the reaction extensively during his synthesis of Halichondrin B, to great effect.

During a rather long synthesis we were trying to convert an aldehyde to a cis-diene using the NHK reaction as one of the steps. For various reasons we were locked into using the chromous chloride from one particular supplier and they kept us a larger quantity of that batch for our future use. As far as I remember the Ni content was not specified but here the quality of chromous chloride is obviously critical for the success of this reaction and it had not been adequately defined. Indeed this may be a reason for the extreme variability we observed during a scale-up campaign that was in direct contrast to the previous campaign, where all the batches went to completion, without problems, in 2 hours at room temperature.

Now each of the three batch reactions behaved differently, the first was not complete after 2 hours and required more (20%) CrCl2 to be added with stirring for 18 hours at RT before it was complete.

Because of this hiccup, prior to the second batch we made sure that the reaction started by taking a small sample and running it in the lab. It behaved as we expected it worked. However, the second batch reaction did not budge one inch. Having a keen eye for detail I observed that the samples taken from the reactor for reaction monitoring had all proceeded rapidly to completion by the time it took to get them to the analytical lab, about ten to fifteen minutes. It was rationalised by others and myself that this may have been an effect due to the contact of the sample with air (oxygen). So here was the answer, take 150,000 mL samples and let them react. However, the others did not like this idea and suggested that we could/should introduce air into the reaction vessel! Two things to note here; 1) air (oxygen) is normally deadly for this type of reaction and 2) the introduction of air into a reactor full of 150 L of THF is a procedure that is fraught with hazard and should not be attempted at home, never mind the pilot plant. But the batteries were obviously in the correct way and lo and behold the reaction went to completion after a further 18-hour period.

The third batch, however, when run under the conditions used for the second batch (extra chromous chloride and a catalytic amount of air) did not move at all. As a last resort it was warmed to 40°C and obliged us by going to completion within 2 hours! I might add at this point that all the reagents and starting materials were use-tested before starting the larger scale batches, no problems were observed, all reactions going to completion within the allotted 2-hour period. I should also point out that the aldehyde was not that stable, as these things tend to be, we did see decomposition and racemisation after stability experiments, and we were running out of chromous chloride so we could not afford to fool around indefinitely.

The reason for this extreme variability and discrepancy from the lab results remains a total mystery and will need to be examined before any further scale-up is planned. However, it is known that catalytic quantities of nickel (II) or palladium (II) may be required for an efficient coupling process. We did not examine the nickel (II) content of our chromous chloride but this is a point we filed for future reference.

Furthermore the chromium residues cannot be present in the wastewater from the process therefore they must be re-cycled for an ecologically sound process although at this stage of development we did not investigate this. Truthfully I would not have known how to start doing this re-cycling and the above sentence is there for effect only. I would guess that somewhere in the literature I would find a paper referencing the preparation of an insoluble chromium(III) salt. I did not look, because the project died and I moved on to better things.

So in the words of the Bard, it is “just like cooking”.

By October 25, 2012 0 comments synthetic chemistry


Macrolactonization: Now here is a word to strike fear into the heart of any synthetic organic chemist. It’s usually the last step, or one of the last steps in a long complicated natural product synthesis. Not much material left to experiment with so each crumb of unreacted starting material, usually the seco-acid has to be recovered. So which method do you choose? Off to the library may no longer be required, as recently Campagne etal have kindly updated their comprehensive review on the subject1 containing 860 references and covering the literature in the review up to 2011.

Upon reading this I was astounded with the number of methods, obviously I was acquainted with some of them, even done a few in the lab, but the scope here is tremendous. There are some 26 or so methods discussed in this review. Which begs the question: Which one do you choose? Stick with the older well-documented ones or go for a newer method? Well it obviously depends upon your molecule and its functionality. I will just pick out some of the reactions discussed, mainly those I am not so well acquainted with and hope that you will find something useful for your own synthesis.

Let’s begin by looking at macrolactonizations by the Boeckman method. This is based on the known formation of ketenes by thermolysis of dioxolenones2. The conditions are mild and hydroxy or amino groups can trap the ketene. Here is the general idea:

Boeckman3 applied it in the following step note the high dilution.

A testimony to the power of this approach is the next example described by Hoye etal4 demonstrating impressive  impressive regioselectivity.

Moslin5a-d described an elegant approach, in his synthesis of (+)-acutiphycin, which employed a retro-ene reaction of an alkynyl ether to produce the ketene.


The Yamaguchi method6 remains one of the most popular procedures for macrolactonization. According to the reviewers more that 340 papers have been published using this method. This, of course, uses the Yamaguchi reagent; 2,4,6-trichlorobenzoyl chloride in the presence of triethylamine to form the mixed anhydride, the triethylamine hydrochloride is filtered and the solution concentrated. After dilution the mixed anhydride solution is added to a very dilute hot (80°C) solution of 2 – 5 equivalents of DMAP. This method is usually excellent for large ring lactones the efficiency falling off as the ring size diminishes. A disadvantage of the method is the use of high temperatures and DMAP conditions that can lead to isomerization and epimerization. As is usually the case with such methods there have been many variations described and the reader is referred to reference 1 for more information.

The Mitsunobu reaction7 a-c has also successfully found it’s way into this chemistry and the success is nicely demonstrated by the formation of the strained 9-membered lactone moiety of griseoviridin8.

Normally high dilution is required for these reactions. Recently a method appeared which does not require high dilution. It was described by White and co-workers9 and relies on some catalytic palladium chemistry (if you call 30 mol% catalytic) and proceeds via an intramolecular allylic oxidation. This has been used for the synthesis of lactones of ring sizes between 14 and 19. The example shown here is part of a deoxyerythronolide B synthesis and proceeds in reasonable yield without the high dilution requirement. However, in order to obtain the 56% yield quoted the starting materials must be re-cycled.

So there it is another very useful review article on a challenging topic. The list of contents is mind-boggling never mind the content itself. If you are in the macrolactonization business I can recommend this tome to you it may just help solve that knotty problem you’ve been having for the last six months.


  1.  Parenty, A., Moreau, X. and Campagne, J. M., Chemical Reviews, 2012, Articles ASAP, DOI: 10.1021/cr300129n, 24/9/2012.
  2.  Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem. 1984, 49, 5105.
  3.  Boeckman, R. K., Jr.; Pruitt, J. R. J. Am. Chem. Soc. 1989, 111, 8286.
  4.  Hoye, T. R.;  Danielson, M. E.;  May, A. E.;  Zhao, H.  Angew. Chem., Int. Ed. Engl. 2008, 47, 9743.
  5. a Liang, L.; Ramaseshan, M.; MaGee, D. I.  Tetrahedron 1993, 49, 2159. b Magriotis, P. A.; Vourloumis, D.; Scott, M. E.; Tarli, A. Tetrahedron Lett. 1993, 34, 2071. c Moslin, R. M.; Jamison, T. F. , J. Am. Chem. Soc. 2006, 128, 15106.d Moslin, R. M.; Jamison, T. F.,  J. Org. Chem. 2007, 72, 9736.
  6. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
  7. a Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett. 1976, 2455.  b Mitsunobu, O. Synthesis 1981, 1.
(734) Hughes, D. L. Org. React. 1992, 42, 335. c Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551.
  8. Kuligowski, C.; Bezzenine-Lafollee, S.; Chaume, G.; Mahuteau, J.; Barriere, J.-C.; Bacque, E.;  Pancrazi, A.; Ardisson, J. J. Org. Chem. 2002, 67, 4565.
  9. Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006, 128, 9032.